Data from the I-SPY 2 trial, presented at the 2017 meeting of the American Society of Clinical Oncology (ASCO), showed a tripling of the estimated pCR rate in the pembrolizumab arm in women with TNBC and a near tripling of the pCR rate in women with HR-positive/HER2-negative breast cancer, compared with women who received standard neoadjuvant therapy without pembrolizumab, reported Rita Nanda, MD, Assistant Professor of Medicine and Associate Director of Breast Medical Oncology at the University of Chicago, Illinois.

“Of note, in the 7-year history of I-SPY 2, this is the first agent that has graduated for HR-positive disease,” she said.

Regimens in I-SPY 2 that show a high Bayesian predictive probability of being more effective than standard therapy are said to have “graduated” from the trial, with the goal being to test them and their corresponding biomarker signatures in larger trials.

I-SPY 2 is a standing adaptively randomized, controlled, multicenter phase 2 trial in which novel neoadjuvant therapies are evaluated in women with newly diagnosed, locally advanced breast cancer (stage II/III) with the primary end point being pCR. Agents in I-SPY 2 graduate based on an 85% probability of a successful 1:1 randomized 300-patient phase 3 trial with pCR as an end point. Thirteen agents to date have been investigated in multiple concurrent experimental arms.

“Adaptive randomization minimizes the number of patients needed to determine efficacy,” said Dr Nanda.

The I-SPY 2 data presented at ASCO were based on results observed in patients at high risk for relapse using up-front tumor profiling (including HR status, HER2 status, and the MammaPrint 70-gene signature test). Eligible patients had a tumor size ≥2.5 cm, were candidates for preoperative chemotherapy, and were willing to undergo serial magnetic resonance imaging (MRI) and biopsies. In this arm of I-SPY 2, patients were treated with weekly paclitaxel (80 mg/m2) for 12 weeks, with or without pembrolizumab, followed by doxorubicin and cyclophosphamide every 3 weeks for 4 cycles. Sixty-nine patients were adaptively randomized to receive pembrolizumab 200 mg every 3 weeks for 4 weeks, from December 2015 until it graduated in November 2016. Forty-six patients have undergone surgery, whereas the other 23 have on-therapy MRI assessments. There were 180 controls who received chemotherapy only.

Adding pembrolizumab to paclitaxel increased the estimated pCR rate (defined as no residual invasive cancer in the breast or lymph nodes) on an intent-to-treat basis from 20% to 60% in patients with TNBC, and from 13% to 34% in patients with HR-positive, HER2-negative breast cancer compared with standard therapy. In patients with HER2-negative breast cancer, an absolute increase of 30% was observed in the estimated pCR rate in the pembrolizumab arm based on the estimated pCR rate of 46% with pembrolizumab plus standard therapy versus 16% with standard therapy alone. No statistical analysis was performed—the trial was conducted to estimate the probability that a regimen would be superior to control.

In the TNBC arm, the improvement in estimated pCR “translated to a >99% probability of pembrolizumab being superior to the control arm, and the predicted probability of success in a randomized phase 3 trial of >99%,” Dr Nanda noted. The predictive probability of success in a phase 3 trial also exceeded 99% in all patients with HER2-positive disease, and was 88% in those with HR-positive, HER2-negative breast cancer.

Based on the Bayesian predictive probability of success in a confirmatory phase 3 trial, pembrolizumab has graduated from I-SPY 2 for all signatures for which it was tested (TNBC, all HER2-negative cancers, and HR-positive, HER2-negative cancers).